Parasympathicolytically active alpha, alpha-diphenyl-gamma-dialkylaminobutyramide compounds and manufacture thereof



PARASYMPATHICOLYTICALLY ACTIVE ALPHA,

ALPHA DIPHENYL-GAMlVIA-DIALKYLAMINO- BUTYRAMIDE COB [POUNDS AND MANUFAC- TURE THEREOF Paul Adriaan Jan Janssen, Turnhout, Belgium, and David Karel de Jongh, Haarlem, Netherlands, assignor to N-V. Nederlandsche Combinatie voor Chemische Industrie, Amsterdam, Netherlands, a Dutch company No Drawing. Application August 3, 1955 Serial No. 526,314

Claims priority, application Netherlands August 28, 1954 2 Claims. (Cl. 260-457) This invention relates to certain alpha,alpha-diphenyl gamma-dialkylamiuo butyramides and their quaternary ammonium-salts which we have found to be highly potent and highly specific parasympathicolytically active compounds. The compounds of this invention are of especial utility as inhibitors of gastric secretion in man.

It is a principal object of this invention to provide parasympathicolytically active compounds which have the aforesaid utility and which have little or no side efilects.

Compounds have heretofore been proposed for the purposes aforesaid but have many side effects when administered in man. Thus known compounds heretofore proposed have exhibited side effects as dizziness and orthostatic hypotension at therapeutically active doses which made them unsuitable for human administration. Moreover, these known com- 1 pounds never exhibited an inhibitory action on histamininduced gastric secretion in man. i

It is another object of this invention to provide parasympathicolytically active compounds which have the aforesaid utility and are more active icity than the said known compounds. The compounds herein disclosed exhibit a large activity and a very low toxicity when administered by the oral route in the prevention of gastric secretion.

The parasympathicolytic activity of alpha,alpha-diphenyl-gamma-dialkylamino butyramides was known (Arch. exp. Med. Ass. 151, 798 (1953), and Gastroenterology 23, 199 (1953)). Kirsner et al. (Gastroenterology 23, 199 (1953), and J. Am. Med. Ass. 151, the compounds alpha,alpha-diphenyl-gamma-N-piperidino butyramide and its methiodide to possess strong inhibitory action on gastric secretion. However, owing to side effects these compounds were deemed as unsuitable for therapeutic use.

According to this invention, it has foregoing objectives and advantages are realized by certain new compounds, i.e., compounds selected from the group consisting of alpha,a1pha-diphenyl-gamma-alkylisopropylamino butyramides and their quaternary ammonium salts.

The alpha,alpha-diphenyl-gamma-alkylisopropylamino butyramides may be represented by the following formula:

and lower in toxvirtue of the reactions involved are caused to occur at R Pharmakol. u. Pathol. 214, 93 (1951), I. Am.

798 (1953)), found 1 2,884,436 Patented Apr. 28, 195-9 ice wherein R isalkyl; their quaternaryammonium salts by the formula:

omen:

wherein R and R are alkyl and X is an acidic radical- A preferred example of the foregoing is alpha,alphadiphenyl-gamma-diisopropylamino butyramide methio-. dide, whose parasympathicolytic action is at least two times that of alpha,alpha-diphenyl-gamma-N-piperidino' butyramide, which is the strongest active alpha,alphadiphenyl-gamma-dialkylamino butyramide described up} till now. Given orally, the toxicity is exceedingly low, the LB (mice) being two to three times as large as for' the known alpha,alpha-diphenyl-gamma-dialkyl-amino butyramides. The inhibitory actionit exhibits on histamin-induced gastric secretion in man is a property which was not described for any known compounds.

Other examples of preferred alkyl radicals which may I be represented by R in the foregoing formulae are methyl and ethyl. R is preferably represented by methyLethyl drawbacks because of the v and isopropyl. 2

The compounds of this invention may be prepared in: any suitable manner. However, it has been foundthat the preferred method of preparing the compounds is by. the hydrolysis of the corresponding nitriles. It also has been found that the nitriles are preferably obtained by one of the following processes: r

(1) By, condensing an alkyl isopropyl amineywith al-l pha,alpha-diphenyl-gamma-halogen butyronitrile;

(2) By condensing alpha,a1pha-diphenylacetonitrile with an alkyl isopropyl aminoethylhalide. With reference to the methods referred to-above, the alkyl groups in the alkyl isopropyl amine or in the alkyl isopropyl aminoethylhalide correspond to those which by butyramides can be converted into their quaternary am-- monium salts by boiling them under reflux withan alkyl-' halide or another alkyl ester. However, if an alpha, alpha-diphenyl-gamma-dialkylamino butyramide is con-' verted into its quaternary ammonium salt by boiling with an isopropyl ester the yields are low. It was found that these yields could be considerably raised by carrying out this quaternisation in a closed vessel under pressure.

The hydrolysis of the nitriles is preferably carried out inthe presence of a mineral acid, sulfuric acid normally giving the best results.

The invention will be further explained by reference to the following examples:

Example 1 nitrile in ml. of benzene was slowly added with stirring,-

the temperature of the mixture being 3()-35 ,Aftet all of the "diph'enyl acetonitrile had been added themixture was heated to boiling and boiled under reflux for 45 minutes. After cooling, a solution of 28 grams of diisopropylaminoethylchloride in 40 ml. of xylene is added dropwise, the temperature of the mixture again being 3035 C. When this addition has been completed, the mixture is boiled under reflux for a period of three hours. After cooling, washing with water, extraction with hydrochloric acid, alkalifying with sodium hydroxide, extraction with ether, drying and evaporation of the ether, theremaining oil is distilled in vacuo. 50 grams of an oil with, a boiling rangeof l60200 C. at a pressure of 0.5-4.0 mm. mercury are obtained.

20 grams of this alpha,alpha-d-iphenyl-gamma-diisopropylamino butyronitrile are dissolved in 40 ml. of 90% sulfuric acid and boiled for three hours under reflux. eaction. mixture is poured into ice water and made al a me withIO 'Nsodium hydroxide. At first an oil s ep'arateg which solidifies at C. Theprecipitate is filtered,fwashed with water and recrystallized from aqueous-ethanol. The resulting purified product is alpha, alph iphenyl-g'amma-diisopropylamine butyramide with antelt'ingipoint "of "'84 '0.

Example 2 1 9-.2"-grams or diisopropylamine and 28.6grams of alph'a'mlpha -diphe'nyl gamma bromobutyronitrile, dissolved in 60 ml. of xylene are boiled under reflux for a week. "Diisop'ropylammoniumbromide precipitates and is washed with ether after filtration. The ether and the xylenels olutions are'un-ited and evaporated on a water bath. The remainder is extracted with 3 N hydrochloric acid,'-'th'e'"' x'tract 'made alkaline with 10 N sodiumhydroxi'iie a tiow extracted 'with ether. After drying and y'apora'tionbfthe' ether the'residue is distilled in vacuo. Thedilfwas obtained in'a'yield of 5 to 10%. The same yield'ssare 'obtaiiiedwhen the nitrile is boiled for a week with a large excess of diisopropylamine without addition of a solvent. "The obtained 'alpha,-alpha-diphenyl-gammadiisopropylar'nin'o butyronitrile is converted to the corresponding amide according to the procedure described above in Example '1. The resulting product was the saiheas that *obtaiiicd in Example 1.

Example 3 .I:9.2'-J'grams 'ofdiisopropyl amine "and 28.5 .grams of alpha,alpha diphenyl gamma bromobutyronitrile, disv solvedi'in 605ml. "of :xylene are heated :for a period of eight hoursatzatemperature of 120 Cuin-a sealed tube. The:"diisopropylammoniumbromide thus'formed precipitates and isfiltered'ofiand washed with ether. The ether and" the xylene solutions .are united and evaporated on a wateribath. The remainder is extracted with 3N hydrochloric acid, the extract made alkaline with 10 N sodium hydroxideanduo'w extracted with ether. After drying and" evaporation "of the ether:the.residue is distilled in vacuo. The :oil "isnow obtained in a yield of 86%. This alpha,alpha diphenyl-gamma-diisopropylaminobutyronitrile is converted -tothe corresponding amide according to'the proceduredescnbed above in Example 1. The-same-exid-product was obtained.

' "Example '4 The procedure of Example 1 was followed, except that instead of diisopropylaminoethylchloridep 23 grams of methylisopropylaminoethylchloride was used. Thenitrile was obtained .ini'a yield of. 93%. The resulting product was alpha,alpha-diphenyl-garnma-methylisopropylamino butyramide with a melting point of 152 C.

ExiimpleS T he procedure of Example 2 was followed," except that insteadlof difopropyl'amine 15.8 grams of'methyl isopropylamine' was nsed. iThe'fnitrile'was obtained'in a yield" of 10% .v The result-ing'product 1 was the "same as obtained in Example 4.

4. Example 6 The procedure of Example 3 was followed, except that instead of diisopropylamine 15.8 grams of methyl is0- propyl amine was used. The nitrile was obtained in a yield of 89%. The resulting product was the same as obtained in Example 4.

Example 7 The procedure of Example 1 was followed, except that instead of d-iisopropylaminoethylchloride 25.6 grams of ethyl isopropyl aminoethylchloride was used. The nitrile was obtained in a yield of 89%. The resulting product was I alpha,alpha-diphenyl-gamma-ethylisopropylamino butyramide with a melting point of 115 C.

Example 8 The procedure of ExampleZ was followed, exceptthat insteadof 'diisopropylam-ine18.'5 grams of ethyl isopropyl amine was used. The nitrile was obtained in a yield of 5%. The resulting product was the same as obtained in Example 7.

Example 9 The procedure of Example 3 was followed, except that instead of diisopropylamine 18.5 grams of ethyl isopropyl amine was used. The nitrile Was obtained in a yield of 87%. The) resulting product was the same as obtained in Example 7.

Example 10 The procedure of Example 10 was followed, except that instead of methyl iodide dimethyl sulfate was used. The resulting product was alpha',alpha diphenyI-gammadiisopropylm'ethylammonium butyramide sulfate.

Example 12 'Thep'rocedure'of Example 10 was followed, except that insteadbf alpha,alpha diphenybgamma-diisopropylamino butyramide and methyl iodide alpha,alpha-diphenylgamma-methylisopropylamino butyramide and methyl bromidewas used. The resulting product was alpha,- alpha-diphenyl-gamrna-dimethylisopropylammoniurn butyramidebromide.

Example 13 'The procedure of Example 10 was followed, except that instead of alpha,alpha-diphenyl-gamma-diisopropyl'amino 'butyramide and methyl iodide alpha,alpha-diphenylgamma-ethylisopropylamino butyramide and methyl bromide was used. Theresulting product was alpha,alphadiphenyl-gamma-methyl-ethylisopropylammonium butyramide bromide.

Example 14 5 grams'of alpha,alpha-diphenyl-gamma-dimethylamino butyramide, 15 ml. of isopropyl bromide and 40 ml. of isopropanol are heated for 6 hours at C. in a closed vessel. Thereafter the solvent and the excess of isopropyl bromide are "evaporated in vacuo and the residue is washed several times with boiling ethyl acetate. The resulting product is the same as obtained'in'Example 12.

Example 15 The procedure of- Example 14 was followed,-except that instead of alpha,alpha-diphenyl-gamma-dimethylamino buty-ramide a1pha,alphadiphenyl-gamma-methylethylamino butyramide was used. The resulting product is the same as obtained in Example 13.

The amides obtained can be used on account of their strongly pronounced parasympathicolytic activity as therapeutic agents, e.g., for inhibition of gastric secretion, on the one hand, and as intermediates for further syntheses on the other.

In order for the preferred properties to be obtained the number of carbon atoms in the alkyl radicals should not be in excess of four.

We claim:

1. In a method comprising reacting an alpha,alpha-diphenyl-gamma-alkyl isopropylamino butyramide with an alkyl ester of a mineral acid to form a quaternary ammonium salt of said butyramide containing a non-toxic mineral acid radical and recovering said quaternary ammonium salt, the step of efiecting the reaction at a temperature at least of the order of 110 C. to 120 C. in a closed system under pressure.

2. In a method comprising reacting an alpha,alpha-diphenyl-gamma-alkyl isopropylamino butyramide with an alkyl ester of a mineral acid to form a quaternary ammonium salt of said butyramide containing a non-toxic mineral acid radical and recovering said quaternary ammonium salt, the improvement which consists of efiecting the reaction at an elevated temperature, in a closed system at superatmospheric pressure.

References Cited in the file of this patent UNITED STATES PATENTS 2,647,926 Specter Aug. 4, 1953 2,823,233 Specter Feb. 11, 1958 FOREIGN PATENTS 504,085 Belgium July 14, 1951 OTHER REFERENCES 

1. IN A METHOD COMPRISING REACTING AN ALPHA,ALPHA-DIPHENYL-GAMMA-ALKYL ISOPROPYLAMINO BUTYRAMIDE WITH AN ALKYL ESTER OF A MINERAL ACID TO FORM A QUATERNARY AMMONIUM SALT OF SAID BUTYRAMIDE CONTAINING A NON-TOXIC MINERAL ACID RADICAL AND RECOVERING SAID QUATERNARY AMMONIUM SALT, THE STEP OF EFFECTING THE REACTION AT A TEMPERATURE AT LEAST OF THE ORDER OF 110*C. TO 120*C. IN A CLOSED SYSTEM UNDER PRESSURE. 